FOCUSED (Femtosecond Optimized Continuous Uncorrected Sight with EDOF and Diffractive Multifocal IOLs) - A Review.

PURPOSE OF REVIEW: The aim of this article is to review techniques to maximize all-distance uncorrected visual acuity and minimize photic phenomena after the implantation of multifocal and extended-depth of focus (EDOF) intraocular lenses (IOLs). This review examines the role of femtosecond laser-assisted cataract surgery (FLACS) in postoperative minimization of astigmatism and optimization of outcomes with multifocal and EDOF lenses. RECENT FINDINGS: By incorporating intraoperative and preoperative imaging, femtosecond platforms such as those that utilize iris or conjunctival vessel registration, can enable a precision of corneal incisions and toric IOL markings that enable the lowest possible postoperative levels of astigmatism. Current studies suggest that with increasing IOL complexity, that is, trifocal versus bifocal, image degradation with even low levels of postoperative astigmatism are increased. To this end, current data support the utility of femtosecond laser arcuate incisions to enable the achievement of 0.5 D or less postoperative astigmatism for best outcomes with multifocal lenses. SUMMARY: The synergistic combination of multifocal/EDOF IOLs with FLACS is an extremely promising route in achieving postoperative spectacle independence for patients. The marriage of the precision of FLACS with the increasing complexity of multifocal/EDOF IOLs will fuel nomogram adjustment and systematic improvements, such as the Wörtz-Gupta formula. Such strategies provide an unprecedented precision to cataract surgery that makes FOCUSED (Femtosecond Optimized Continuous Uncorrected Sight with EDOF and Diffractive Multifocal IOLs) a reality.

Magnetic resonance-guided, real-time targeted delivery and imaging of magnetocapsules immunoprotecting pancreatic islet cells.

In type I diabetes mellitus, islet transplantation provides a moment-to-moment fine regulation of insulin. Success rates vary widely, however, necessitating suitable methods to monitor islet delivery, engraftment and survival. Here magnetic resonance-trackable magnetocapsules have been used simultaneously to immunoprotect pancreatic beta-cells and to monitor, non-invasively in real-time, hepatic delivery and engraftment by magnetic resonance imaging (MRI). Magnetocapsules were detected as single capsules with an altered magnetic resonance appearance on capsule rupture. Magnetocapsules were functional in vivo because mouse beta-cells restored normal glycemia in streptozotocin-induced diabetic mice and human islets induced sustained C-peptide levels in swine. In this large-animal model, magnetocapsules could be precisely targeted for infusion by using magnetic resonance fluoroscopy, whereas MRI facilitated monitoring of liver engraftment over time. These findings are directly applicable to ongoing improvements in islet cell transplantation for human diabetes, particularly because our magnetocapsules comprise clinically applicable materials.

X-ray-visible microcapsules containing mesenchymal stem cells improve hind limb perfusion in a rabbit model of peripheral arterial disease.

The therapeutic goal in peripheral arterial disease (PAD) patients is to restore blood flow to ischemic tissue. Stem cell transplantation offers a new avenue to enhance arteriogenesis and angiogenesis. Two major problems with cell therapies are poor cell survival and the lack of visualization of cell delivery and distribution. To address these therapeutic barriers, allogeneic bone marrow-derived mesenchymal stem cells (MSCs) were encapsulated in alginate impregnated with a radiopaque contrast agent (MSC-Xcaps). In vitro MSC-Xcap viability by a fluorometric assay was high (96.9% ± 2.7% at 30 days postencapsulation) and as few as 10 Xcaps were visible on clinical x-ray fluoroscopic systems. Using an endovascular PAD model, rabbits (n = 21) were randomized to receive MSC-Xcaps (n = 6), empty Xcaps (n = 5), unencapsulated MSCs (n = 5), or sham intramuscular injections (n = 5) in the ischemic thigh 24 hours postocclusion. Immediately after MSC transplantation and 14 days later, digital radiographs acquired on a clinical angiographic system demonstrated persistent visualization of the Xcap injection sites with retained contrast-to-noise. Using a modified TIMI frame count, quantitative angiography demonstrated a 65% improvement in hind limb perfusion or arteriogenesis in MSC-Xcap-treated animals versus empty Xcaps. Post-mortem immunohistopathology of vessel density by anti-CD31 staining demonstrated an 87% enhancement in angiogenesis in Xcap-MSC-treated animals versus empty Xcaps. MSC-Xcaps represent the first x-ray-visible cellular therapeutic with enhanced efficacy for PAD treatment.

Retinal microenvironment imbalance in dry age-related macular degeneration: a mini-review.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in the western world. To prevent what will certainly be a tremendous health and economic burden, effective therapeutics for AMD are urgently needed. To develop these agents in a timely fashion, the molecular pathways that cause disease progression must be elucidated. OBJECTIVE: To briefly describe the clinical features of AMD, and review the current understanding of the molecular basis of AMD. METHODS: A literature review. RESULTS: The discussion will primarily focus on the interplay of oxidative stress and complement dysregulation and the resulting chronic proinflammatory state thought to be central in AMD pathogenesis. CONCLUSIONS: Oxidative stress and complement dysregulation play a substantive role in the development of AMD.

Solving STODS-Surgical Temporary Ocular Discomfort Syndrome.

The term STODS (Surgical Temporary Ocular Discomfort Syndrome) has been coined to describe the ocular surface perturbations induced by surgery. As one of the most important refractive elements of the eye, Guided Ocular Surface and Lid Disease (GOLD) optimization is fundamental to success in achieving refractive outcomes and mitigating STODS. Effective GOLD optimization and the prevention/treatment of STODS requires an understanding of the molecular, cellular, and anatomic factors that influence ocular surface microenvironment and the associated perturbations induced by surgical intervention. By reviewing the current understanding of STODS etiologies, we will attempt to outline a rationale for a tailored GOLD optimization depending on the ocular surgical insult. With a bench-to-bedside approach, we will highlight clinical examples of effective GOLD perioperative optimization that can mitigate STODS' deleterious effect on preoperative imaging and postoperative healing.

Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging.

PURPOSE: To develop novel immunoprotective alginate microcapsule formulations containing perfluorocarbons (PFCs) that may increase cell function, provide immunoprotection for xenografted cells, and simultaneously enable multimodality imaging. MATERIALS AND METHODS: All animal experiments were approved by an Institutional Animal Care and Use Committee. Cadaveric human islet cells were encapsulated with alginate, poly-l-lysine, and perfluorooctyl bromide (PFOB) or perfluoropolyether (PFPE). In vitro viability and the glucose-stimulation index for insulin were determined over the course of 2 weeks and analyzed by using a cross-sectional time series regression model. The sensitivity of multimodality (computed tomography [CT], ultrasonography [US], and fluorine 19 [(19)F] magnetic resonance [MR] imaging) detection was determined for fluorocapsules embedded in gel phantoms. C57BL/6 mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) islet-containing fluorocapsules and control mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) fluorocapsules without islets were monitored for human C-peptide (insulin) secretion during a period of 55 days. Mice underwent (19)F MR imaging at 9.4 T and micro-CT. Swine (n = 2) receiving 9000 PFOB capsules through renal artery catheterization were imaged with a clinical multidetector CT scanner. Signal intensity was evaluated by using a paired t test. RESULTS: Compared with nonfluorinated alginate microcapsules, PFOB fluorocapsules increased insulin secretion of encapsulated human islets, with values up to 18.5% (3.78 vs 3.19) at 8-mmol/L glucose concentration after 7 days in culture (P < .001). After placement of the immunoprotected encapsulated cells into mice, a sustained insulin release was achieved with human C-peptide levels of 19.1 pmol/L ± 0.9 (standard deviation) and 33.0 pmol/L ± 1.0 for PFPE and PFOB capsules, respectively. Fluorocapsules were readily visualized with (19)F MR imaging, US imaging, and CT with research- and clinical-grade imagers for all modalities. CONCLUSION: Fluorocapsules enhance glucose responsiveness and insulin secretion in vitro, enable long-term insulin secretion by xenografted islet cells in vivo, and represent a novel contrast agent platform for multimodality imaging.

Fluorine (19F) MRS and MRI in biomedicine.

Shortly after the introduction of (1)H MRI, fluorinated molecules were tested as MR-detectable tracers or contrast agents. Many fluorinated compounds, which are nontoxic and chemically inert, are now being used in a broad range of biomedical applications, including anesthetics, chemotherapeutic agents, and molecules with high oxygen solubility for respiration and blood substitution. These compounds can be monitored by fluorine ((19)F) MRI and/or MRS, providing a noninvasive means to interrogate associated functions in biological systems. As a result of the lack of endogenous fluorine in living organisms, (19)F MRI of 'hotspots' of targeted fluorinated contrast agents has recently opened up new research avenues in molecular and cellular imaging. This includes the specific targeting and imaging of cellular surface epitopes, as well as MRI cell tracking of endogenous macrophages, injected immune cells and stem cell transplants.

Assessment of EmboGel--a selectively dissolvable radiopaque hydrogel for embolic applications.

PURPOSE: To evaluate the embolic properties of an alginate-based embolic biomaterial (EmboGel) and its solvent (EmboClear) in treatment of aneurysms. MATERIALS AND METHODS: EmboGel is a mixture of iohexol and alginate that polymerizes into a hydrocoil when delivered through a coaxial catheter with a distal mixing tip, exposing alginate to a calcium chloride solution. In contrast to previously reported embolic agents, EmboGel can be selectively dissolved by EmboClear, a mixture of the enzyme alginate lyase and ethylenediaminetetraacetic acid (EDTA). The embolic and contrast properties of EmboGel were assessed in in vitro models of saccular aneurysm and an aortic aneurysm endoleak. The dissolvability of EmboGel with EmboClear was assessed further after endovascular delivery in the New Zealand white rabbit in the native aortoiliofemoral territory, a created saccular aneurysm, and the native carotid arteries. RESULTS: EmboGel effectively filled aneurysm cavities in the case of stent excluded saccular and fusiform aneurysms. EmboGel was readily dissolved by EmboClear in vitro and after in vivo embolization. When the distal abdominal aorta and pelvic arteries were occluded with EmboGel, within 1 minute of EmboClear infusion, patency of the aorta and most of the pelvic circulation was regained as noted by angiography. Embolization in the subclavian artery and numerous distal branches was rapidly dissolved by EmboClear. Finally, the carotid artery occluded with EmboGel regained patency after administration of EmboClear. CONCLUSIONS: EmboGel is a dissolvable alginate-based biomaterial that can be used for numerous embolic applications. EmboGel can be selectively dissolved with EmboClear, a solution of alginate lyase and EDTA.

Dupilumab-Associated Mucin Deficiency (DAMD).

Purpose: Dupilumab, a monoclonal antibody directed against the interleukin-4 receptor subunit α (IL-4Rα) of IL-4 and IL-13, is increasingly being used to control atopic disease. Dupilumab use has been associated with a poorly understood conjunctivitis. In this study, we sought to investigate the hypothesis that dupilumab use and the associated IL-13 blockade causes a relative ocular mucin deficiency. Methods: Tear levels of mucin 5ac (Muc5AC) and total tear protein levels were evaluated from 28 eyes of 14 patients. Bilateral tear samples were acquired from seven patients on dupilumab and seven patients with no exposure to dupilumab. Study subjects were age and gender matched. In addition to tear samples, photographic documentation of ocular surface findings and a questionnaire of ocular surface symptoms were obtained. Between-group mean differences were calculated. Results: Compared with control, ocular Muc5AC levels normalized to total tear protein was statistically significantly lower. The average Muc5AC levels for persons on dupilumab was 1.54 ± 0.58 ng/mg and that of controls was 7.99 ± 1.16 ng/ mg. Persons on dupilumab reported a statistically increased occurrence of ocular fatigue/eye strain, uncomfortable sensation, pain, red eye, and itching. Conclusions: This study demonstrates for the first time, a relative deficiency of Muc5AC in patients on dupilumab. Translational Relevance: The results of this study support the previously reported role of IL-13 in increasing goblet cell density and associated Muc5AC production. Further efforts are underway to better understand the relative contribution of Muc5AC deficiency in the overall presentation of conjunctivitis associated with dupilumab use.

Potential of Ocular Transmission of SARS-CoV-2: A Review.

PURPOSE OF REVIEW: to provide a prospective on the current mechanisms by which SARS-CoV-2 enters cells and replicates, and its implications for ocular transmission. The literature was analyzed to understand ocular transmission as well as molecular mechanisms by which SARS-CoV-2 enters cells and replicates. Analysis of gene expression profiles from available datasets, published immunohistochemistry, as well as current literature was reviewed, to assess the likelihood that ocular inoculation of SARS-CoV-2 results in systemic infection. RECENT FINDINGS: The ocular surface and retina have the necessary proteins, Transmembrane Serine Protease 2 (TMPRSS2), CD147, Angiotensin-Converting Enzyme 2 (ACE2) and Cathepsin L (CTSL) necessary to be infected with SARS-CoV-2. In addition to direct ocular infection, virus carried by tears through the nasolacrimal duct to nasal epithelium represent a means of ocular inoculation. SUMMARY: There is evidence that SARS-CoV-2 may either directly infect cells on the ocular surface, or virus can be carried by tears through the nasolacrimal duct to infect the nasal or gastrointestinal epithelium.

Rationale for American Society of Retina Specialists Best Practice Recommendations for Conducting Vitreoretinal Surgery during the COVID-19 Era.

PURPOSE: To detail the rationale behind recommendations recently published by the American Society of Retina Specialists (ASRS) outlining best practices for safety of vitreoretinal surgeons and staff while performing vitreoretinal surgery during the coronavirus disease (COVID)-19 pandemic. METHODS: The committee for ASRS Best Practices for Retinal Surgery during the COVID-19 Pandemic reviewed existing evidence and information on SARS-CoV-2 transmission, and risk factors during vitreoretinal surgery. Recommendations were based on best available published data, cumulative clinical experiences, and recommendations and policies from other organizations. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the strength of recommendations and confidence in the evidence. These serve as interim recommendations which are routinely updated given gaps of knowledge and lack of high-quality data on this evolving subject. RESULTS: Relevant existing literature related to methods of transmission, and ocular manifestations of SARS-CoV-2 are summarized. The data and clinical experiences driving recommendations for pre-operative, intraoperative and post-operative surgical considerations, anesthesia choice, as well as considerations for intravitreal injections are provided. CONCLUSION: Recommendations are provided with the goal of protecting vitreoretinal surgeons and associated personnel from exposure to SARS-CoV-2 during interventional vitreoretinal procedures. This is a rapidly evolving topic with numerous remaining gaps in our current knowledge. As such, recommendations will evolve and the current manuscript is intended to serve as a foundation for continued dialogue on best practices.

In vitro assessment of EmboGel and UltraGel radiopaque hydrogels for the endovascular treatment of aneurysms.

PURPOSE: To describe two hydrogel embolic materials, the alginate-based EmboGel and the polyethylene glycol diacrylate-based UltraGel and examine their use as embolic agents in in vitro models of abdominal aortic aneurysm (AAA) endoleak and saccular aneurysms. MATERIALS AND METHODS: EmboGel is a mixture of iohexol and alginate, with a calcium chloride solution used to induce polymerization. UltraGel is a mixture of igracure, iohexol, and polyethylene glycol diacrylate and polymerizes in the presence of ultraviolet (UV) light. Modified microcatheter delivery systems were used in both cases to demonstrate use of the hydrogels in fusiform and saccular aneurysm models. RESULTS: Preliminary in vitro results suggest that EmboGel and UltraGel provide effective embolization in fusiform and saccular aneurysm models, respectively. Due to the rapid polymerization of EmboGel, the agent was delivered in a strand-like form. When used in conjunction with a stent in an AAA endoleak model, this form was able to effectively fill the aneurysmal cavity and occlude it from the central blood flow. UltraGel, conversely, was delivered as a liquid and slowly polymerized in the presence of UV light. This system in a saccular aneurysm model was able to form a solid cast inside the aneurysm wall, again showing complete occlusion from the parent flow. CONCLUSIONS: Preliminary results indicate these two novel hydrogel applications may prove effective for the treatment of saccular and fusiform aneurysms.

Novel approach to a type I endoleak following a hybrid repair of an arch aortic aneurysm.

Hybrid surgical and endovascular approaches such as open visceral vessel debranching and subsequent endovascular exclusion of thoracic abdominal aortic aneurysms (TAAA) represents a significant development in treatment of TAAAs. As compared to traditional endovascular aneurysm repair, hybrid repairs commonly have a higher rate of endoleak and other endograft-related complications. In this report, we present a 71 year-old man with significant comorbidities including chronic obstructive pulmonary disease, hypertension and prostate cancer. The patient after undergoing debranching of the thoracic arch followed by endograft repair of an arch aneurysm developed a proximal type I and type II endoleak fed by the previously ligated left subclavian artery. Despite coiling of the left subclavian artery and proximal extension of the endograft, a type I endoleak persisted. Several months after the left subclavian artery was coiled, a catheter was advanced through the coils and beyond the site of ligation directly into the aneurysmal sac. Once in the aneurysmal sac, multiple coils were deployed resulting in successful treatment of the type I endoleak. This report highlights the unique challenges in treating proximal descending thoracic aneurysms and represents the first report of the treatment of a type I endoleak with reaccess through a previously coiled vessel for deployment of embolics directly into the aneurysmal sac.

Cytopathologic analysis of paratracheal masses: a study of 737 cases with clinicoradiologic correlation.

OBJECTIVE: To analyze the cytopathologic findings of a series of paratracheal space (PTS) masses in the context of clinicoradiologic correlation. STUDY DESIGN: Retrospective review of our cytopathology files revealed 131 cases of PTS lesions in a 14-year period (1991-2005). Cytologic material was obtained under radiologic guidance. Radiologic findings, clinical data and subsequently performed tissue biopsies were reviewed and correlated. RESULTS: Radiologic imaging disclosed masses in the PTS ranging from 1 to 7 cm. Of the 131 cases, 103 (79%) were deemed diagnostic. Of these, 41 (40%) revealed nonneoplastic lesions, and 62 (60%) yielded malignant neoplasms. Nonneoplastic entities included: 31 (73%) hyperplastic lymph nodes and 10 (24%) sarcoidosis. Of the malignant cases, 45 (73%) were metastatic tumors: adenocarcinoma (ACA) 19, small cell carcinoma 12, squamous cell carcinoma (SQCC) 11 and other tumors, from lung 34, esophagus 4 and other sites. Malignant neoplasms from local spread included lung non-small cell carcinoma 6, SQCC 3 and ACA 3, papillary thyroid carcinoma 3 and other 2. CONCLUSION: Fine needle aspiration (FNA) of PTS has a high diagnostic yield (79%) with a sensitivity of 97% and specificity of 100%. The most common diagnosis is a malignant tumor (60%), with metastatic carcinoma (73%) the most common neoplasm (lung ACA the most common primary source). The most common benign entity is a hyperplastic lymph node (24%). Ancillary studies (immunoctyochemistry, fluorescence in situ hybridization and electron microscopy) were helpful and provided definitive diagnosis in 30% of the initially nondiagnostic FNA samples.

Catheter-directed gastric artery chemical embolization suppresses systemic ghrelin levels in porcine model.

PURPOSE: To prospectively test, in a porcine model, the hypothesis that catheter-directed gastric artery chemical embolization (GACE) can result in suppression of systemic ghrelin levels and affect weight gain. MATERIALS AND METHODS: This study, which had Animal Care and Use Committee approval, was performed in healthy, growing swine (weight range, 40-45 kg; n = 10). GACE was performed in five swine with the infusion of sodium morrhuate (125 mug) selectively into the gastric arteries that supply the fundus. Five control animals underwent a sham procedure with 5 mL of saline. Weight and fasting plasma ghrelin levels were obtained in animals at baseline and in weeks 1-4. Statistical testing for substantial differences in ghrelin blood levels over time and between treated and untreated animals was performed by using a cross-sectional time-series linear model with feasibility generalized least squares. RESULTS: The pattern of the change in ghrelin levels over time was significantly different between control and treated animals (P < .004). In treated animals, ghrelin levels were significantly reduced at week 1 (mean, 664.1 pg/mL +/- 103.1 [standard error of the mean], P < .02), week 2 (mean, 618.1 pg/mL +/- 180.4, P < .001), week 3 (mean, 578.4 pg/mL +/- 214.9, P < .001), and week 4 (mean, 876.6 pg/mL +/- 228.6, P < .03) relative to baseline (mean, 1006.3 pg/mL +/- 190.1). The percentage change in serum ghrelin values in swine treated with GACE decreased from baseline to -34%, -38.6%, -42.5%, and -12.9% during weeks 1-4, respectively. In control swine, percentage change in serum ghrelin was -1.7%, -9.7%, +2.6%, and +18.2% during weeks 1-4, respectively. At the end of 4 weeks, control swine continued to gain weight, with a 15.1% increase from their original weight, while the weight in swine treated with GACE plateaued at an increase of 7.8% from the original weight. CONCLUSION: Catheter-directed GACE can suppress the appetite hormone ghrelin and affect weight gain.

Evolution of Leukemic Retinal Hemorrhages Documented by Spectral-Domain OCT and Color Fundus Photography.

PURPOSE: Retinal hemorrhages are observed frequently in patients with leukemia. However, little is known about the impact and natural history of these hemorrhages. The purpose of this study was to describe leukemic retinal hemorrhages using multimodal imaging and to monitor their evolution longitudinally. DESIGN: Retrospective case series. PARTICIPANTS: A total of 11 eyes of 7 symptomatic leukemic patients with posterior segment hemorrhages. METHODS: Single-center study performed at the Johns Hopkins Hospital. Symptomatic leukemic patients with posterior segment hemorrhages underwent serial dilated fundus examinations. The hemorrhages were documented longitudinally with color fundus photographs and spectral-domain (SD) OCT. MAIN OUTCOMES MEASURES: Microanatomic locations of leukemic retinal hemorrhages and their impact on vision and evolution over time. RESULTS: A total of 7 patients (71.4% men; 57.1% white, 28.6% black, and 14.3% Hispanic) were included, with 11 eyes showing posterior segment hemorrhages. The median age at presentation was 49.8 years. All patients had intraretinal hemorrhages; these involved the vitreous and sub-internal limiting membrane (ILM) space in 1 and 3 patients, respectively. The median total follow-up duration was 4.0 months. At the final follow-up visits, 4 of 6 patients showed complete resolution of hemorrhages on examination and color fundus photographs. The final SD-OCT images of all patients did not show any retinal thinning, disruption of the ellipsoid zone, disorganization of the retinal layers, intraretinal fluid, or subretinal fluid. CONCLUSIONS: Symptomatic leukemic retinal hemorrhages are associated with anemia and thrombocytopenia. These hemorrhages, including visually significant central sub-ILM hemorrhages, tend to be self-limiting and resolve within a few months with treatment of the underlying disease.

Noninvasive Tracking of Alginate-Microencapsulated Cells.

This chapter presents a description of standardized techniques used routinely in our laboratory to encapsulate different cell types using the alginate-PLL-alginate immunoisolation system. Given the importance of noninvasive tracking of encapsulated cell transplants, we present a detailed guidance to achieve maximum efficiency and functionality of the capsule preparations for optimal tracking posttransplantation. The provided protocols cover tracking of encapsulated cells using magnetic resonance (MR), X-ray, computed tomography (CT), and ultrasound (US) imaging. Practical suggestions to optimize each method with specific references to recommended suppliers are included.

Vision concerns after mild traumatic brain injury.

OPINION STATEMENT: Mild traumatic brain injury (mTBI) can manifest with visual dysfunction including deficits in accommodation, vergence movements, versions, and field of vision as well increased photosensitivity and a decline in ocular and overall health. Patients with incomitant strabismus should be referred to an ophthalmologist for intervention. Patients with mTBI who experience photosensitivity, or deficits in accommodation, versions, vergences, or field of vision may benefit from vision rehabilitation. These therapies may include spectacles with tinting and a variety of prism combinations. Patients with chronic visual dysfunction following mTBI may benefit from occupational, vestibular, cognitive, and other forms of physical therapy.